Rickettsia Infections

Rickettsial diseases (rickettsioses): Various illnesses caused by rickettsiae and manifested by sudden onset, a course of fever of one to several weeks, headache, malaise, prostration, peripheral vasculitis, and, in most cases, a characteristic rash.

Rickettsioses comprise four groups: typhus--epidemic typhus, Brill-Zinsser disease, murine (endemic) typhus, and scrub typhus; spotted fever--Rocky Mountain spotted fever, Eastern tick-borne rickettsiosis, and rickettsialpox; Q fever; and trench fever. Ehrlichiosis is caused by Ehrlichia, a rickettsia-like bacteria transmitted to humans by ticks.

Most members of the order Rickettsiales are obligate intracellular pleomorphic coccobacilli. They are true bacteria as they have metabolic enzymes and cell walls, use O₂, and are susceptible to antibiotics, although they require living cells for growth. Most rickettsiae are maintained in nature by a cycle involving an animal reservoir and an insect vector (usually an arthropod) that infects humans. Because many rickettsiae are localized to certain geographic areas, a knowledge of where the patient lives or has recently traveled often helps in diagnosis.

Some rickettsiae multiply at the site of an arthropod attachment and produce a local lesion (eschar). They penetrate the skin or mucous membranes and multiply in the endothelial cells of small blood vessels, causing a vasculitis consisting of endothelial proliferation, perivascular infiltration, and thrombosis. The endovasculitis causes the rash, encephalitic signs, and gangrene of skin and tissues.

Differential Diagnosis of Rickettsial Diseases

Differentiating rickettsioses from other acute infectious diseases is difficult during the first several days before the rash appears. A history of louse or flea infestation or tick bite in known endemic areas of rickettsioses is helpful. Any seriously ill patient who lives in or near a wooded area and has unexplained fever, headache, and prostration, with or without a history of tick contact, should be suspected of having Rocky Mountain spotted fever (RMSF).

In meningococcemia, the rash may be pink, macular, maculopapular, or petechial in the subacute form and petechially confluent or ecchymotic in the fulminant form; it resembles RMSF or epidemic typhus. The meningococcal rash develops rapidly in acute disease and, when ecchymotic, usually is tender on palpation; the rickettsial rash usually appears on about the 4th febrile day and gradually becomes petechial over several days.

In rubeola, the rash begins on the face, spreads to the trunk and arms, and soon becomes confluent; RMSF thus may be confused with rubeola. The rash of rubella usually remains discrete. Postauricular lymph nodes and lack of toxicity favor rubella.

In murine typhus, which is milder than RMSF or epidemic typhus, the rash is nonpurpuric, nonconfluent, and less extensive; renal and vascular complications are uncommon. However, differentiating RMSF from murine typhus may be difficult, and specific serologic testing may be required. Treatment should not be delayed until this distinction is made.

Epidemic louse-borne typhus causes all the profound physiologic and pathologic abnormalities of RMSF, including peripheral vascular collapse, shock, cyanosis, ecchymotic skin necrosis, digital gangrene, azotemia, renal failure, delirium, and coma. The rash of epidemic typhus usually appears first over the axillary folds and trunk; later it spreads peripherally, rarely involving the palms, soles, and face.

Local eschars occur in patients with scrub typhus, rickettsialpox, and, occasionally, the spotted fevers. The epidemiologic history often helps in differentiation. The rash in rickettsialpox is vesicular; in tick-borne typhus, it is often obviously maculopapular. In Q fever, a rash is unusual; in trench fever, sparse. In ulceroglandular tularemia (associated with an eschar) and other forms of tularemia, there is no exanthem. Lyme disease, in which the characteristic erythema chronicum migrans rash often occurs, should also be considered.

Rickettsialpox is mild; usually an initial eschar occurs at the point of the mite attachment, and the rash, in the form of vesicles with surrounding erythema, is sparse. Because similar oral lesions occur in varicella, it must be ruled out.

Patients with scrub typhus have all the clinical and pathologic manifestations of RMSF and epidemic typhus; however, scrub typhus occurs in different geographic areas, particularly in Malaya and northern Thailand. Frequently, an eschar develops with satellite adenopathy.

Laboratory tests: Serologic tests, isolation and identification of Rickettsia rickettsii from blood or tissues, and identification of the agent in skin or other tissues by immunofluorescence help confirm the diagnosis, particularly in RMSF. To be useful, serologic tests require three serum samples, taken during the 1st, 2nd, and 4th to 6th wk of illness. Polymerase chain reaction is useful in early identification of specific rickettsial nucleic acids.

Complement fixation reaction: The serologic patterns of RMSF and typhus are distinctive in specific rickettsial antigens. Spotted fever and typhus group rickettsiae have two types of complement fixation (CF) antigens; the soluble fraction is common to all members of the group, whereas purified fractions are more specific for individual rickettsiae. Various spotted fevers (eg, RMSF, rickettsialpox, fièvre boutonneuse, North Asian tick-borne rickettsiosis, Queensland tick typhus) may be distinguished by type-specific washed rickettsial-body antigen. Antibodies in response to a primary infection of RMSF and typhus are usually IgM type. CF antibodies appear in patients during the 2nd and 3rd wk of these illnesses and later in those treated with antibiotics within the first 3 to 5 days of illness. Under these circumstances, a later convalescent specimen should be taken at 4 to 6 wk. In Brill-Zinsser disease, type 7S antibodies appear rapidly after several days of illness. Q-fever antigens are specifically diagnostic. In acute infections, antibodies to phase 2 antigens appear; phase 1 antibodies indicate chronic infection (eg, hepatitis, endocarditis).

Other serologic tests: Using purer antigens, other serologic tests for rickettsioses not only distinguish between specific infections but also help determine the type of immunoglobulin in acute (IgM) and late or recurrent (IgG) illnesses, such as Brill-Zinsser disease. CF tests are useful for routine diagnosis; microscopic agglutination, indirect fluorescent antibody (IFA), and hemagglutination reactions are valuable for identification and are becoming standard. IFA and CF tests help confirm trench fever. R. akari shares a common antigen with other members of the spotted fever group but can be differentiated by demonstration of a rising titer of specific CF antibodies. R. conorii, R. sibirica, and R. australis share a common antigen with R. rickettsii and R. akari but are differentiated by CF and mouse toxin neutralization tests as well as by cross-immunity tests in guinea pigs.

Immunofluorescence techniques have been used to detect R. rickettsii and R. prowazekii in tissues of chick embryos, guinea pigs, and vector ticks. Identifiable rickettsiae have been seen in skin lesions of patients with RMSF as early as the 4th day of illness or as late as the 10th day. Rickettsiae may be stained by IFA technique in formalin-fixed tissues.

Isolation and identification: Isolation of an organism is rarely needed except for epidemiologic reasons; when attempted, blood should be taken early from febrile patients with spotted or typhus fever before antibiotic treatment. Isolation of causative rickettsia by inoculation of guinea pigs, mice, or embryo yolk sacs has generally been replaced with various tissue culture techniques.

Treatment of Rickettsial Diseases

All rickettsioses require specific chemotherapy and supportive care. Measures advisable for all infections are described here; variations are described below for ehrlichiosis, rickettsialpox, Q fever, and trench fever.

Symptoms and signs are promptly alleviated if therapy begins early, when the rash first appears. Since untreated patients with RMSF may become moribund or die before definitive serologic data are available, treatment should begin as soon as a presumptive diagnosis is made. Obvious clinical improvement is usually noted within 36 to 48 h, with defervescence in 2 to 3 days. In scrub typhus, the response is even more dramatic.

Tetracyclines and chloramphenicol are specifically effective; they are rickettsiostatic, not rickettsicidal. Optimal regimens include an initial oral dose of tetracycline 25 mg/kg or chloramphenicol 50 mg/kg. Subsequent daily doses of the same amount are divided equally and given at 6- to 8-h intervals until the patient improves and has been afebrile for about 24 h. IV preparations are used in those too ill to take oral medication.

In patients first treated during the later stages, improvement is slower and fever is of longer duration. Patients seriously ill with a rickettsial disease of the typhus and spotted fever group often have circulatory collapse, oliguria, anuria, azotemia, anemia, hyponatremia, hypochloremia, edema, and coma. In mildly and moderately ill patients, these alterations are absent, making management less complicated. Critically ill patients who are first seen late in the course of severe illness may be given large doses of corticosteroids in combination with specific antibiotics for about 3 days.

Severely ill patients with RMSF and epidemic typhus may have a marked increase in capillary permeability in later stages; IV fluids should be given cautiously to avoid worsening pulmonary and cerebral edema. Heparin is not recommended in patients with disseminated intravascular coagulation.